Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we examined the expression of cyclins, cyclin dependent kinase (CDKs) and CDK inhibitors by immunohistochemical analysis in 20 normal mucosa, 42 epithelial dysplasia (ED), and 117 oral squamous cell carcinoma. Neither Cyclin D1 nor CDK2 were detectable in normal tissue and ED. Their presence, however, was detectable in squamous cell carcinoma (SCCs) (Cyclin D1, 35.9%; CDK2, 66.7%). Cyclin E was detectable in 57.1% of severe ED and 62.8% of SCCs. For the CDK inhibitors, these proteins were detectable in all normal mucosa and most of the mild and moderate ED. For severe ED, expression of these proteins was not observed in some cases (p12(DOC-1), 14.3%; p16(INK4A), 28.6%; p27(KIP1), 7.1%). For SCCs, the expression of p12(DOC-1) was lost in 71.8%, p16(INK4A) in 69.2% and p27(KIP1) in 35.9%. These results suggest that elevated expression of cyclin D1, cyclin E, CDK2 and loss of p12(DOC-1), p16(INK4A) and p27(KIP1) may contribute to the multistep nature of oral carcinogenesis.
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PMID:Expression of cell cycle control proteins in normal epithelium, premalignant and malignant lesions of oral cavity. 1197 45

Karyotypic alterations, including whole chromosome loss or gain, ploidy changes, and a variety of chromosome aberrations are common in cancer cells. If proliferating cells fail to coordinate centrosome duplication with DNA replication, this will inevitably lead to a change in ploidy, and the formation of monopolar or multipolar spindles will generally provoke abnormal segregation of chromosomes. Indeed, it has long been recognized that errors in the centrosome duplication cycle may be an important cause of aneuploidy and thus contribute to cancer formation. This view has recently received fresh impetus with the description of supernumerary centrosomes in almost all solid human tumors. As the primary microtubule organizing center of most eukaryotic cells, the centrosome assures symmetry and bipolarity of the cell division process, a function that is essential for accurate chromosome segregation. In addition, a growing body of evidence indicates that centrosomes might be important for initiating S phase and completing cytokinesis. Centrosomes undergo duplication precisely once before cell division. Recent reports have revealed that this process is linked to the cell division cycle via cyclin-dependent kinase (cdk) 2 activity that couples centriole duplication to the onset of DNA replication at the G(1)/S phase transition. Alterations in G(1)/S phase regulating proteins like the retinoblastoma protein, cyclins D and E, cdk4 and 6, cdk inhibitors p16(INK4A) and p15(INK4B), and p53 are among the most frequent aberrations observed in human malignancies. These alterations might not only lead to unrestrained proliferation, but also cause karyotypic instability by uncontrolled centrosome replication. Since several excellent reports on cell cycle regulation and cancer have been published, this review will focus on the role of centrosomes in cell cycle progression, as well as causes and consequences of aberrant centrosome replication in human neoplasias.
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PMID:Centrosome replication, genomic instability and cancer. 1198 36

Preneoplastic and neoplastic hepatocytes undergo c-Myc up-regulation and overgrowth in rats genetically susceptible to hepatocarcinogenesis, but not in resistant rats. Because c-Myc regulates the pRb-E2F pathway, we evaluated cell cycle gene expression in neoplastic nodules and hepatocellular carcinomas (HCCs), induced by initiation/selection (IS) protocols 40 and 70 weeks after diethylnitrosamine treatment, in susceptible Fisher 344 (F344) rats, and resistant Wistar and Brown Norway (BN) rats. No interstrain differences in gene expression occurred in normal liver. Overexpression of c-myc, Cyclins D1, E, and A, and E2F1 genes, at messenger RNA (mRNA) and protein levels, rise in Cyclin D1-CDK4, Cyclin E-CDK2, and E2F1-DP1 complexes, and pRb hyperphosphorylation occurred in nodules and HCCs of F344 rats. Expression of Cdk4, Cdk2, p16(INK4A), and p27(KIP1) did not change. In nodules and/or HCCs of Wistar and BN rats, low or no increases in c-myc, Cyclins D1, E, and A, and E2F1 expression, and Cyclin-CDKs complex formation were associated with p16(INK4A) overexpression and pRb hypophosphorylation. In conclusion, these results suggest deregulation of G1 and S phases in liver lesions of susceptible rats and block of G1-S transition in lesions of resistant strains, which explains their low progression capacity.
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PMID:Cell cycle deregulation in liver lesions of rats with and without genetic predisposition to hepatocarcinogenesis. 1202 19

We have characterized the cell cycle deficit of a novel TrkA receptor mutant (TrkAS3) that fails to support nerve growth factor (NGF)-dependent cell cycle arrest and neurite outgrowth. TrkAS3 receptors fail to support an NGF-dependent increase in the expression of cyclin D1 and the cell cycle inhibitor, p21(Waf1/Cip1), two important regulators of G(1) /S transition, and do not down-regulate expression of the G(2) /M phase marker, cdc2/cdk1, or the S phase marker, proliferating cell nuclear antigen. Moreover, NGF-activated TrkAS3 receptors do not down-regulate cyclin-dependent kinase 4 phosphorylation of the retinoblastoma protein, essential for G(1) arrest, in comparison to NGF-activated wild-type TrkA. Collectively these data indicate that TrkAS3 receptors fail to support NGF-dependent G(1) arrest. Interestingly, ectopic expression of regulators of G(1) /S arrest, such as cyclin D1 or inhibitors of cell cycle (p21(Waf1/Cip1), p16(INK4A) ), or the fibroblast growth factor (FGF) receptor substrate-2 (FRS2) in cells expressing TrkAS3 reconstitutes NGF-dependent neurite outgrowth. Collectively, these data suggest a model in which NGF-stimulated TrkA-dependent activation of FRS2 supports neurite outgrowth through a mechanism that likely involves the induction of p21(Waf1/Cip1) expression and the arrest of cells at G(1) /S.
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PMID:Overexpression of the signaling adapter FRS2 reconstitutes the cell cycle deficit of a nerve growth factor non-responsive TrkA receptor mutant. 1206 41

With increasing frequency during serial passage in culture, primary human keratinocytes express p16(INK4A) (p16) and undergo senescence arrest. Keratinocytes engineered to express hTERT maintain long telomeres but typically are not immortalized unless, by mutation or other heritable event, they avoid or greatly reduce p16 expression. We have confirmed that keratinocytes undergo p16-related senescence during growth in culture, whether in the fibroblast feeder cell system or in the specialized K-sfm medium formulation, and that this mechanism can act as a barrier to immortalization following hTERT expression. We have characterized the p16-related arrest mechanism more precisely by interfering specifically with several regulators of cell cycle control. Epidermal, oral mucosal, corneal limbal, and conjunctival keratinocytes were transduced to express a p16-insensitive mutant cdk4 (cdk4(R24C)), to abolish p16 control, and/or a dominant negative mutant p53 (p53DD), to abolish p53 function. Expression of either cdk4(R24C) or p53DD alone had little effect on life span, but expression of both permitted cells to divide 25 to 43 population doublings (PD) beyond their normal limit. Keratinocytes from a p16(+/-) individual transduced to express p53DD alone displayed a 31-PD life span extension associated with selective growth of variants that had lost the wild-type p16 allele. Cells in which both p53 and p16 were nonfunctional divided rapidly during their extended life span but experienced telomere erosion and ultimately ceased growth with very short telomeres. Expression of hTERT in these cells immortalized them. Keratinocytes engineered to express cdk4(R24C) and hTERT but not p53DD did not exhibit an extended life span. Rare immortal variants exhibiting p53 pathway defects arose from them, however, indicating that the p53-dependent component of keratinocyte senescence is telomere independent. Mutational loss of p16 and p53 has been found to be a frequent early event in the development of squamous cell carcinoma. Our results suggest that such mutations endow keratinocytes with extended replicative potential which may serve to increase the probability of neoplastic progression.
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PMID:A two-stage, p16(INK4A)- and p53-dependent keratinocyte senescence mechanism that limits replicative potential independent of telomere status. 1207 43

Treatment of MCF 7 cells with the fungal estrogen zearalenone induced cyclin E-associated kinase activity transiently within 9-12 h; total cyclin-dependent kinase (Cdk) 2 activity was elevated for 24 h and beyond. This increased cyclin E/Cdk2 activity was associated with sequestration of the Cdk inhibitor p27 Cdk inhibitor 1B (p27(KIP1)) by newly formed cyclin D1/Cdk4 complexes and with downregulation of p27(KIP1) expression. The activation of cyclin A/Cdk2 activity corresponded with virtual elimination of p27(KIP1). The activity of cyclin E/Cdk2 complexes from zearalenone-treated lysates was inhibited in vitro by recombinant p27(KIP1), and this inhibition was relieved by the addition of recombinant cyclin D1/Cdk4 complexes. Thus, sequestration of p27(KIP1) by cyclin D1/Cdk4 resulted in activation of Cdk2 in vitro. Cdk inhibitory activity in lysates of zearalenone-treated cells was depleted by anti-p27(KIP1) and anti-Cdc2 interacting protein (p21(CIP1)) antibodies. Overexpression of the Cdk4/6-specific Cdk inhibitor of Cdk4 p16(INK4A) was associated with increased association of p27(KIP1) with Cdk2, concomitant with disruption of D cyclin/Cdk4 complexes. The proteasome inhibitor 2-leu-leu-leu-H aldehyde (MG-132) was relatively ineffective in inhibiting the initial, sequestration-dependent activation of cyclin E/Cdk2 yet was as effective as p16(INK4A) in inhibiting activation of cyclin A/Cdk2 later in G(1). Downregulation of p27(KIP1) proceeded in p16(INK4A)-expressing cells after zearalenone treatment, and G(1) arrest afforded by p16(INK4A) expression was reversible upon prolonged treatment with zearalenone. Zearalenone treatment of MCF-7 cells elicited expression of F-box protein S phase kinase-associated protein 2 (p45(SKP2)), a substrate-specific component of the ubiquitin-ligase complex that targets p27(KIP1) for degradation in the proteasome. These studies suggest that both sequestration of Cdk inhibitors by cyclin D1/Cdk4 complexes and downregulation of p27(KIP1) play major roles in the induction of Cdk2 activity and S phase entry elicited by estrogens in MCF-7 cells.
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PMID:Removal of Cdk inhibitors through both sequestration and downregulation in zearalenone-treated MCF-7 breast cancer cells. 1211 22

Granulosa cell tumors (GCTs) of the ovary are relatively rare and account for <5% of all ovarian cancers. The molecular pathogenesis of these tumors is not well understood. We tested the hypothesis that cyclin-dependent kinase inhibitors, specifically the inhibitors of the cyclin-dependent kinase 4 (INK4) family, are targets for altered gene expression in GCTs. The status of RB1, INK4A, INK4B, INK4C, INK4D, and ARF in 13 adult and 2 juvenile ovarian GCTs was determined by reverse transcription-polymerase chain reaction of total RNA and exon-specific sequencing of genomic DNA. Tumors showing loss of INK4A expression were assayed further by exon-deletion analysis and methylation-specific PCR. None of the juvenile tumors demonstrated altered expression, but 7/12 (58%) adult GCTs lacked expression of INK4A, INK4B, or both. In one of these cases, we noted a homozygous deletion of the INK4A locus, and in the remaining tumors we found hypermethylation of the promoter region, a mechanism that can lead to gene inactivation. These data support a role for the INK4 family of CDK inhibitors in the biology of GCTs.
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PMID:Evidence of a role for the INK4 family of cyclin-dependent kinase inhibitors in ovarian granulosa cell tumors. 1220 82

Most breast cancers arise from luminal epithelial cells and 25-30% of these tumours overexpress the ErbB-2 receptor. Herein, a non-transformed, immortalized cell system was used to investigate the effects of ErbB-2 overexpression in luminal epithelial cells. The phenotypic consequence of ErbB-2 overexpression is a shortening of the G1 phase of the cell cycle and early S phase entry, which leads to hyperproliferation. We show that this effect was mediated through the up-regulation of cdk6 and cyclins D1 and E, and enhanced degradation and relocalization of p27(Kip1). These changes were effected predominantly through enhanced MAPK signalling, resulting in cdk2 hyperactivation. PI3K signalling also participated in cell cycle progression, since PI3K and MAPK coordinately regulated changes in cyclin D1 and cdk6 expression. Cdk4 activity was not required for cell cycle progression in these cells, and was constitutively inhibited through its association with p16(INK4A). MAPK-dependent induction of p21(Cip1) was also necessary for G1 phase progression, although its degradation by the proteasome was required for S phase entry. These data provide new insights into the complex molecular mechanisms underlying mitogenic cell cycle control in luminal epithelial cells, the cell type relevant to primary breast cancer, and show how ErbB-2 overexpression subverts this normal control.
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PMID:Effects of ErbB-2 overexpression on mitogenic signalling and cell cycle progression in human breast luminal epithelial cells. 1224 55

BACKGROUND: The effects of the vitamin A metabolite retinoic acid (RA) are mediated at the transcriptional level by retinoic acid receptors (RAR). These proteins are part of a superfamily of transcription factors which activate target gene expression when bound to their respective ligands. In addition to ligand binding, heterodimerization with transcriptional cofactors and posttranslational modification such as phosphorylation are also critical for transactivation function. Previous studies have shown that phosphorylation of a serine residue at amino acid 77 in the RARalpha amino terminus was required for basal activation function of the transcription factor. RESULTS: We have determined that RA inhibits cyclin H and cdk7 expression thereby decreasing levels of phosphorylated RARalpha in human cancer cell lines. To determine the effects of decreased RARalpha phosphorylation in human cancer cells, we stably transfected a phosphorylation defective mutant RARalpha expression construct into SCC25 cultures. Cells expressing the mutant RARalpha proliferated more slowly than control clones. This decreased proliferation was associated with increased cyclin dependent kinase inhibitor expression and decreased S phase entry. In the absence of ligand, the RARalpha mutant inhibited AP-1 activity to an extent similar to that of RA treated control clones. Levels of some AP-1 proteins were inhibited due to decreased EGFR expression upstream in the signaling pathway. CONCLUSIONS: These results indicate that hypophosphorylated RARalpha can mimic the anti-AP-1 effects of RA in the absence of ligand.
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PMID:A phosphorylation defective retinoic acid receptor mutant mimics the effects of retinoic acid on EGFR mediated AP-1 expression and cancer cell proliferation. 1239 97

Apoptotic cell death is an important mode of cell loss contributing to heart dysfunction. To analyze the importance of the E2F-dependent regulation of gene transcription in cardiomyocyte apoptosis, the function of cell cycle factors impinging on the retinoblastoma protein (pRb)/E2F pathway was investigated. In isolated neonatal ventricular myocytes, apoptotic cell death induced by hypoxia (deferoxamine, 100 micro mol/L) specifically activated cyclin-dependent kinases (cdks) 2 and 3. Apoptotic cell death was inhibited by ectopic expression of cdk inhibitors p21(CIP) and p27(KIP1) but not p16(INK4). In addition, apoptosis was also abrogated by forced expression of kinase dead mutant proteins of cdk2/3 but not of cdk4/6. Introduction of cdk inhibitors or dominant-negative cdk2/3 blocked pRb hyperphosphorylation and abrogated E2F-dependent gene transcription, including that of the E2F-responsive genes of proapoptotic caspase 3 and caspase 7. Moreover, introduction of constitutively active pRb and transcriptionally inert mutant E2F1/DP1 efficiently protected cardiomyocytes from apoptosis. In conclusion, these data demonstrate that cdk-specific inactivation of pRb and the subsequent activation of E2F-dependent gene transcription are required for cardiomyocyte apoptosis.
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PMID:Inhibition of hypoxia-induced apoptosis by modulation of retinoblastoma protein-dependent signaling in cardiomyocytes. 1241 92


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